Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors

Abstract

The neuronal accumulation of phosphorylated tau plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Here, we examined the effect of fisetin, a flavonol, on tau levels. Treatment of cortical cells or primary neurons with fisetin resulted in significant decreases in the levels of phosphorylated tau. In addition, fisetin decreased the levels of sarkosyl-insoluble tau in an active GSK-3β-induced tau aggregation model. However, there was no difference in activities of tau kinases and phosphatases such as protein phosphatase 2A, irrespective of fisetin treatment. Fisetin activated autophagy together with the activation of transcription factor EB (TFEB) and Nrf2 transcriptional factors. The activation of autophagy including TFEB is likely due to fisetin-mediated mammalian target of rapamycin complex 1 (mTORC1) inhibition, since the phosphorylation levels of p70S6 kinase and 4E-BP1 were decreased in the presence of fisetin. Indeed, fisetin-induced phosphorylated tau degradation was attenuated by chemical inhibitors of the autophagy-lysosome pathway. Together the results indicate that fisetin reduces levels of phosphorylated tau through the autophagy pathway activated by TFEB and Nrf2. Our result suggests fisetin should be evaluated further as a potential preventive and therapeutic drug candidate for AD.

Fisetin Prevents Acetaminophen-Induced Liver Injury by Promoting Autophagy

“…We note that autophagy activity was significantly reduced when compared to controls. A previous study has shown that FST promoted autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors (Kim et al, 2016), suggesting that FST exerts pro-autophagy effects. However, another study has also shown that FST exerts autophagy repressing effects (Yen et al, 2017) at doses < 20 µM in tunicamycin-mediated cells.…”

“…In a previous study, we showed that FST alleviates hepatic lipid metabolism through activation of the SIRT1 pathways (Liou et al, 2018). Similarly, FST has been observed to induce autophagy in multi cancers like breast cancer, oral cell carcinoma, and pancreatic cancer (Yang et al, 2012;Kim et al, 2016;Klimaszewska-Wisniewska et al, 2016;Jia et al, 2019;Park et al, 2019). However, the autophagy effects of FST on liver injury are still unclear.…”

Optical induction of autophagy via Transcription factor EB (TFEB) reduces pathological tau in neurons

“…To test the ability of optically induced transgene expression to clear p-Tau, we chose TFEB, which is a well-established regulator of autophagy, and previously implicated in clearing tau via constitutive activation [29,30,53,54]. As a first step, we decided to confirm whether TFEB can clear p-Tau and determine whether TFEB can target multiple forms of p-Tau via autophagic flux in neuronal cells.…”

Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

“…This compound was able to induce autophagy by simultaneously promoting the activation and nuclear translocation of both TFEB and NRF2, along with some of its target genes. This response was prevented by TFEB or NRF2 silencing [125]. Bott and colleagues reported beneficial effects of a simultaneous NRF2, NRF1 and HSF1 activator on protein toxicity in spinal and bulbar muscular atrophy, a neurodegenerative disorder caused by expansion of polyglutamine-encoding CAG repeats in which protein aggregates are present [126].…”